4,4′-(1-methyl-1,2-ethandiyl)-bis-(2,6-piperazinedione) has the general formula (I)

The compound of the formula (I) may be present in the form of two enantiomers as (S)-(+)-4,4′-(1-methyl-1,2-ethandiyl)-bis-(2,6-piperazinedione), also referred to as Dexrazoxan, and as (R)-(−)-4,4′-(1-methyl-1,2-ethandiyl)-bis-(2,6-piperazinedione), also referred to as Levorazoxan, as well as in the form of a racemate, (S,R)-4,4′-(1-methyl-1,2-ethandiyl)-bis(2,6-piperazinedione), also referred to as Razoxan. In conjunction with this invention a “compound of the formula (I)” or “4,4′-(1-methyl-1,2-ethandiyl)-bis-(2,6-p-piperazinedione)”, respectively, refers to the S-enantiomer, the R-enantiomer as well as to the racemate.
Regardless of its stereochemistry the compound of the formula (I) has an antitumor effect. In the past, the S-enantiomer of the compound of the formula (I), Dexrazoxan, which is known to be effective against tumors and other forms of cancer and which is also useful as a synergist in combination with other anticancer agents, has achieved special relevance. Particularly with regard to sarcoma, lymphosarcoma and leukaemia, it has been found that Dexrazoxan shows an activity and is particularly effective when used in a regime together with Adriamycin.
In the prior art several preparation methods for the compound of the formula (I) have been known for a long time. For example, in the U.S. Pat. No. 3,941,790 and No. 4,275,063, to Creighton, three methods for preparing bisdiketopiperazines, wherein the compounds of the formula (I) are also included, are described. In the first method, (S)-1,2-diaminopropane is reacted with chloroacetic acid to form (S)-1,2-diaminopropane-tetraacetic acid. Subsequently tetraacetic acid is reacted with formamide under nitrogen at an elevated temperature to the corresponding compound of the formula (I). In the second method tetraacetic acid is prepared as previously described, transferred to the corresponding tetraacetic acid amide by reacting with ammonia and the latter subsequently cyclizised to polyphosphorous acid or phenol by heating. This method is said to be particularly beneficial, when the tetraacetic acid tends to decarboxylate during heating. As a third method, reacting of a tetranitrile with sodium amide in formamide and the subsequent treating of the resulting product with hydrogen chloride in methanol are mentioned. According to Creighton this alternative method has the benefit to be a low-temperature technique. All these methods are stereoselective methods, i.e. therefore the employed intermediate compounds in the form of tetraacetic acid, tetraamide or tetranitrile should already be available in the stereochemical configuration desired for the compound of the formula (I).
The intermediate compounds employed in the aforementioned methods, such as tetraacetic acid, may be prepared in different ways. Beside the already aforementioned preparation methods, for example, in British Patent No. 978.724, J.R., to Geigy A G, a method for forming tetraacetic acid is described, wherein diamines are reacted with formaldehyde and hydrogen cyanide to form a tetranitrile, which is saponified. In U.S. Pat. No. 2,461,519, Bersworth et al., they teach a method for preparing 1,2-diaminopropane-tetracarboxylic acid by reacting 1,2-diaminopropane with formaldehyde and sodium cyanide at an alkaline pH-value.
A main problem with the preparation of the compound of the formula (I) is generally the purification of the intermediate compounds, which is costly and difficult to achieve on a commercial scale. With numerous methods, for example, intermediate compounds, such as tetraacetic acid, are obtained together with high amounts of alkali metal salts as a by-product, which prior to cyclization to the compound of the formula (I) have to be separated.
These problems of the aforementioned preparation methods are particularly based on the fact that the employed tetraacetic acid like the tetraamides, the tetranitriles and the compound of the formula (I) themselves are very polar hydrophilic substances and form salts with the strong bases, as being required in the preparation method. Consequently, this always results in difficulties in the required separation of the non-reacted precursor compounds and the resulting by-products.
The problems arising with and through the purification of the precursor compound in known preparation methods are described in detail in International Patent Application No. 93/08172, to P. L. MacDonald. Thus, to solve these problems, a method for preparing the compound of the formula (I), to be precisely, Deraxozan, is suggested, wherein the latter shall be obtained in high yields without, prior to cyclization to Dexrazoxan, performing a purification of the intermediate tetraacetic acid compound. However, by this method Dexrazoxan is obtained together with higher amounts of salt-by-products, which results in difficulties in the production of salt-free Dexrazoxan.
Beside methods for preparing compounds of the formula (I) or analoguous compounds thereof, wherein tetraacetic acid, tetraamide or tetranitrile are employed as a intermediate product, a method for preparing cis- and trans-cyclopropyl-bis-2,6-(piperazinedione), two compounds which are analoguous to the compound of the formula (I), is also described in the literature, which method processes via the corresponding tetraacetic acid methyl ester as a precursor compound. D. T. Witiak et al, Journal of Medicinal Chemistry, Bd. 20, Nr. 5, pp 630-635 (1977), and Journal of Medicinal Chemistry, Vol. 21, No. 12, pp 1194-1197 (1978), describe the cyclization of the corresponding tetraacetic acid methyl ester in the form of the hydrochloride with an excess of ammonia and sodium methoxide in methanol for preparing the trans-compound. The yield of the desired trans-compound is poor and amounts to only 27% prior to purification. According to the authors, the application of this method for preparing the corresponding cis-compound was not successful: For the preparation of the cis-compound, the tetraacetic acid methyl ester is cyclizised with sodium hydride and formamide in DME. The yield of the trans-compound is quoted with 36.5%.
Witiak et al. suggest tetraacetic acid methyl ester exclusively for the preparation of the aforementioned compounds. There is no evidence in it to employ tetraacetic acid methyl ester compounds as precursor compounds for the preparation of analoguous compounds. Rather, the problems in preparating cis- and trans-isomers of the desired compound suggest that the employment of such compounds as a precursor compound is not readily possible.